The neural basis of itch is poorly understood despite its clinical importance. To address the problem, psychophysical measurements of itch sensation in humans will be compared to neurophysiological measurements of responses in primary afferent and spinothalamic tract (STT) neurons of the monkey. The use of similar experimental protocols in the 3 projects will facilitate the identification of the neural mechanisms of itch in primates. Project 1 will conduct psychophysical studies of itch in humans. An adjective-labeled scale will be used to compare the magnitude and time course of itch and pain sensations evoked by punctate mechanical and heat stimuli and by histamine and cowhage. The effects of these stimuli in evoking itch and itchy skin and the inhibitory effects of painful and non-painful stimuli on itch and itchy skin will be investigated. Project 2 will conduct neurophysiological studies in monkey to determine how primary afferent nerve fibers respond to the same pruritic and nociceptive stimuli used in the psychophysical studies. Single fiber recordings from mechanically insensitive and from mechanically sensitive polymodal nerve fibers will be used to test the hypothesis that subsets of primary afferents respond selectively to pruritic stimuli and provide the peripheral signal for itch sensation. Other properties, such as differences in fiber responses to heat and electrical stimuli will be tested to see if they distinguish candidate pruriceptors from nociceptors. Project 3 will conduct neurophysiological studies in monkey to determine how STT neurons respond to the same pruritic and nociceptive stimuli used in the psychophysical studies. Micro-antidromic stimulation techniques will identify STT neurons that project to either the ventral posterior inferior or posterior nuclei of the thalamus. A search will be made for pruriceptive STT neurons that respond specifically or selectively to pruritic stimuli, become sensitized to stimuli that evoke the characteristics of itchy skin, and whose responses to pruritic stimuli are enhanced or reduced by the non-pruritic stimuli shown in Project 1 to increase or decrease itch. A core providing administration, instrumentation, statistics and informatics will facilitate the collection, analysis and evaluation of the data obtained from each project. By increasing our understanding of the peripheral and central neural mechanisms that code and modulate itch, our combined studies will provide new targets for novel therapies to relieve itch.